Genetic factors play a considerable role in nicotine addiction. The present proposal addresses the molecular neuroadaptive processes that mediate the switch from initial nicotine exposure to addiction. Inbred mouse strains, which are highly sensitive to acute nicotine exposure, develop tolerance to chronic nicotine and provide a model for examining the mechanisms underlying the switch from acute nicotine exposure to addiction. C3H, DBA/2, and C57BL/6 mice represent low-, moderate-, and high-nicotine sensitive strains, respectively. Alterations in nicotinic acetylcholine receptors only partially explain the differential effects of acute and chronic nicotine in these strains. Nicotine modulates multiple neurotransmitter systems. The present proposal examines the molecular neuroadaptations in neurotransmitters that occur after acute and chronic nicotine exposure in C3H, DBA/2, and C57BL/6 mice. C3H, DBA/2, and C57BL/6 mice will be continuously infused with nicotine or saline for 6 hr or 10 days. Whole brain will be removed and mRNA phenotype assessed by gene microarray and expression changes validated by quantitative RT-PCR and in situ hybridization. Genotypic and phenotypic changes in mRNA expression in neurotransmitter biochemical pathways will be characterized. Determination of the differential effects of acute and chronic nicotine on gene expression may provide insight into the molecular neuroadaptations that underlie the switch from acute nicotine exposure to nicotine addiction in humans.